The genetic support for the causal relationship between 91 circulating inflammatory proteins and pneumothorax: A two-sample mendelian randomization study
Heart & Lung, 2025
Zhou C., Zhang R.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Respiratory Diseases | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Background
Pneumothorax, a common pleural disease, has an unclear pathogenesis. Observational studies suggest that inflammation may directly or indirectly contribute to the development of pneumothorax.
Objectives
To investigate the causal relationship between circulating inflammatory proteins and pneumothorax using Mendelian randomization (MR) analysis.
Methods
We conducted a two-sample Mendelian randomization (MR) analysis by combining genome-wide association study (GWAS) data on 91 circulating inflammatory proteins with pneumothorax GWAS data. Five MR methods were applied: Inverse Variance Weighted (IVW), MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. Directionality was assessed using the MR Steiger test. Sensitivity analyses included Cochran’ s Q test, the MR-PRESSO global test, the MR-Egger regression intercept test, and a leave-one-out analysis. To further mitigate confounding, multivariable MR analyses were conducted using GWAS data on biological and phenotypic age as covariates.
Results
Four inflammatory proteins were causally associated with pneumothorax. Protective proteins included Interleukin-17A (IL-17A) [OR = 0.83, 95 % CI (0.69, 0.99), p = 0.04] and SIR2-like protein 2 (SIRT2) [OR = 0.72, 95 % CI (0.57, 0.93), p = 0.01]. Risk-associated proteins included Interleukin-13 (IL-13) [OR = 1.23, 95 % CI (1.03, 1.47), p = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR = 1.22, 95 % CI (1.02, 1.44), p = 0.02]. Multivariable MR confirmed the robustness of the associations, particularly for IL-13. Sensitivity analyses revealed no substantial pleiotropy or heterogeneity.
Conclusions
The results yield novel perspectives on the etiological association between systemic inflammatory mediators and pneumothorax pathogenesis, potentially identifying candidate biomarkers for risk stratification and therapeutic targeting in pneumothorax management.